Parkinson's disease is a progressive degenerative disorder of the central nervous system characterized by a loss of neurons in a particular region of the brain, the substantia nigra. These neurons, when present, synthesize and release dopamine, the neurotransmitter used in chemical communication with other cells, and are thus referred to as dopaminergic neurons. Symptoms of Parkinson's disease, including rigidity, resting tremor (shaking), poverty of movement (akinesia), slowness of movement (bradykinesia), and changes in gait and posture, can be severely debilitating, causing a profound change in the quality of life for the spouse or caregiver as well as the patient. These parkinsonian symptoms may also be associated with conditions other than classic Parkinson's disease.
The treatment of Parkinson's disease is based on compensating for the lack of dopaminergic neurotransmission caused by the loss of this dopaminergic population of neurons. Classically, the treatment involves the chronic oral administration of levodopa, which is able to cross the blood-brain barrier, unlike dopamine. Levodopa is a prodrug, and is decarboxylated in the brain to form dopamine. This supplementation of dopamine within the brain compensates for the degeneration of neurons that normally synthesize and release dopamine, and provides a relief from the clinical symptoms of the disease. Other drugs may also be given in conjunction with levodopa.
However, after an initial treatment period of 3-6 years, in which an optimal clinical effect of oral levodopa is observed, movement abnormalities appear in approximately 40-60% of patients. These abnormalities consist of involuntary movements during the periods of clinical improvement ("on" phases) and the re-emergence of parkinsonian symptoms at other times ("off" periods).
Several drugs that act at the postsynaptic dopamine receptor have recently been found to alleviate these abnormalities of chronic levodopa therapy and that substantially increase the duration of "on" periods of clinical improvement. The most powerful and effective of these agents, apomorphine, is limited by a short duration of action and side effects that can be circumvented by subcutaneous injection or infusion. Colosimo, C. et al., "Clinical Usefulness of Apomorphine in Movement Disorders", Clinical Neuropharmacology, 17: 243-259 (1994). However, administration of apomorphine by repeated subcutaneous injections or continuous parenteral infusion by pumps is technically difficult, especially for patients whose manual dexterity is devastated by parkinsonian symptoms and the movements abnormalities caused by chronic levodopa treatment. Oral or sublingual administration routes are unsatisfactory due to breakdown of the drug in the liver, stomatitis, and the development of buccal ulcers. No detectable plasma levels of apomorphine were produced by an attempt to administer apomorphine in a cream [Gancher, S. T. et al., "Absorption of Apomorphine by Various Routes in Parkinsonism", Movement Disorders 6(3): 212-216 (1991)].
Transdermal drug delivery devices for the continuous controlled transdermal administration of drugs other than apomorphine are well known. Examples of such devices can be found in U.S. Pat. No. 3,731,683 to Zaffaroni, U.S. Pat. No. 3,797,494 to Zaffaroni, U.S. Pat. No. 4,031,894 to Uhrquhart et al., and U.S. Pat. No. 4,336,243 to Sanvordecker et al. However, heretofore attempts to deliver apomorphine transdermally have not been successful. See, for example, Gancher et al., Ibid at p. 214.
Transdermal drug delivery devices are typically held in contact with the skin by means of a pressure-sensitive adhesive layer and are left in place for a period of 24 hours or longer.
Silicone pressure-sensitive adhesives are effective for holding such transdermal drug delivery systems to the skin for prolonged periods of time. Such silicone pressure-sensitive adhesives are known to be nonirritating and nonsensitizing to the skin, and have been used for the controlled release of nitroglycerin (Nitro-Disc.RTM., G.D. Searle Co., Skokie, Ill.). Other transdermal drug delivery systems have been developed for the delivery of various drugs. For example, the Transderm Scop.RTM. system for the delivery of scopolamine (CIBA-Geigy, Ardsley, N.Y.) utilizes a polyisobutylene pressure-sensitive adhesive layer.
It has now been found that therapeutically effective amounts of apomorphine can be administered transdermally from an applied gel. Use of a silicone based pressure-sensitive adhesive gel matrix which maintains its tack and adherence throughout the administration of the drug provides another novel approach to the transdermal application of apomorphine.